Non-Ahr Gene Susceptibility Loci for Porphyria and Liver Injury Induced by the Interaction of ‘Dioxin’ with Iron Overload in Mice

Abstract

Among the actions of 2, 3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in mice is the induction of hepatic porphyria. This is similar to the most common disease of this type in humans, sporadic porphyria cutanea tarda (PCT). Evidence is consistent with the actions of dioxin being mediated through binding to the aryl hydrocarbon receptor (AHR) with different Ahr alleles in mouse strains apparently accounting for differential downstream gene expression and susceptibility. However, studies of dioxin-induced porphyria and liver injury indicate that the mechanisms must involve interactions with other genes, perhaps associated with iron metabolism. We performed a quantitative trait locus (QTL) analysis of an F 2 cross between susceptible C57BL/6J (Ahr b1 allele) and the highly resistant DBA/2 (Ahr d allele) strains after treatment with dioxin and iron. For porphyria we found

Multiple polymorphic loci determine basal hepatic and splenic iron status in mice

“…In QTL analyses of the hepatic porphyria induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in combination with iron overload, we found a highly significant locus on chromosome 11. 30 QTL on chromosome 11 for hepatic iron level have been reported in searches for modifier genes in Hfe-null mice 17 and in iron levels in chromosome substitution strains. 26 Only a weak hepatic locus was detected in the present study (Fig.…”

“…Where positions differed markedly, this was taken into account when considering candidate genes. Information about SWR allele sizes was obtained as previously described, or primers were selected and tested for polymorphisms 30 and can be obtained from the corresponding author. Pairs of fluorescently labeled primers were purchased from Applied Biosystems (Warrington, UK), and unlabeled primers were synthesized in the University of Leicester.…”

“…Individuals were genotyped using polymerase chain reaction (PCR) amplification of polymorphic microsatellite markers. 30 Positions of markers were based on data of the Whitehead Institute (WI; http://www.broad.mit.edu/cgi-bin/mouse/ index/). In many cases these were Ͻ2 cM different from those of Mouse Genome Informatics (MGI; http://www.…”

“…The extreme iron burden cohorts representing the most useful information for linkage analysis were genotyped for markers spread across the genome (2 or 3 per chromosome at 20-30 cM). 30 Where the evidence was strongest for a QTL or a chromosomal region was of particular interest, further markers were included (if available) and the remainder of the mice genotyped.…”

B2 SINE retrotransposon causes polymorphic expression of mouse 5-aminolevulinic acid synthase 1 gene

“…Although low heme availability can lead to feed-back derepression of ALAS1 transcription it is probably triggered depending on the level of basal expression. Polymorphisms in ALAS1 response to stimuli, such as seen with chemicals and drugs that cause porphyria, might be the reflection of variation in basal expression [15,16].…”